Institute of Genetic Medicine

Newcastle upon Tyne, United Kingdom

Institute of Genetic Medicine

Newcastle upon Tyne, United Kingdom
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Jaffe A.E.,Johns Hopkins Hospital | Gao Y.,Johns Hopkins Hospital | Deep-Soboslay A.,Johns Hopkins Hospital | Tao R.,Johns Hopkins Hospital | And 4 more authors.
Nature Neuroscience | Year: 2015

DNA methylation (DNAm) is important in brain development and is potentially important in schizophrenia. We characterized DNAm in prefrontal cortex from 335 non-psychiatric controls across the lifespan and 191 patients with schizophrenia and identified widespread changes in the transition from prenatal to postnatal life. These DNAm changes manifest in the transcriptome, correlate strongly with a shifting cellular landscape and overlap regions of genetic risk for schizophrenia. A quarter of published genome-wide association studies (GWAS)-suggestive loci (4,208 of 15,930, P < 10 â '100) manifest as significant methylation quantitative trait loci (meQTLs), including 59.6% of GWAS-positive schizophrenia loci. We identified 2,104 CpGs that differ between schizophrenia patients and controls that were enriched for genes related to development and neurodifferentiation. The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS risk loci while not corresponding to CpGs differentiating adolescence from later adult life. These data implicate an epigenetic component to the developmental origins of this disorder. © 2016 Nature America, Inc.

Martin E.A.,Cedars Sinai Medical Center | Barresi R.,Institute of Genetic Medicine | Byrne B.J.,University of Florida | Tsimerinov E.I.,Cedars Sinai Medical Center | And 7 more authors.
Science Translational Medicine | Year: 2012

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective - causing functional muscle ischemia - in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3′,5′-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

Thompson J.R.,University of Leicester | Attia J.,Hunter Medical Research Institute | Minelli C.,Institute of Genetic Medicine
Briefings in Bioinformatics | Year: 2011

The pressure to publish novel genetic associations has meant that meta-analysis has been applied to genome-wide association studies without the time for a careful consideration of the methods that are used. This review distinguishes between the use of meta-analysis to validate previously reported genetic associations and its use for gene discovery, and advocates viewing gene discovery as an exploratory screen that requires independent replication instead of treating it as the application of hundreds of thousands of statistical tests. The review considers the use of fixed and random effects meta-analyses, the investigation of between-study heterogeneity, adjustment for confounding, assessing the combined evidence and genomic control, and comments on alternative approaches that have been used in the literature. © The Author 2011. Published by Oxford University Press.

Burn J.,Institute of Genetic Medicine | Mathers J.,Northumbria University | Bishop D.T.,University of Leeds
Recent Results in Cancer Research | Year: 2013

Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the pro drugsulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months, the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and polyp removal, 48 recruits developed CRC. Of these, 18 received aspirin and 30 received AP; the HR for CRC for aspirin was 0.63 (CI 0.35-1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect: IRR 0.56 (CI 0.32-0.99, p = 0.05). For those who took aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19-0.86 p = 0.02) and the IRR, 0.37 (CI 0.18-0.78 p = 0.008). Combined analysis of all LS cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42-1.00, p = 0.05 and IRR was 0.59 (CI 0.39-0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26-0.79 p = 0.005,) and IRR was 0.42 (CI 0.25-0.72, p = 0.001). Adverse events in the aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or ulcers in the aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend aspirin to all Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses. © 2013 Springer-Verlag Berlin Heidelberg.

Blaum B.S.,University of Tübingen | Hannan J.P.,Aurora University | Herbert A.P.,University of Edinburgh | Kavanagh D.,Institute of Genetic Medicine | And 3 more authors.
Nature Chemical Biology | Year: 2015

The serum protein complement factor H (FH) ensures downregulation of the complement alternative pathway, a branch of innate immunity, upon interaction with specific glycans on host cell surfaces. Using ligand-based NMR, we screened a comprehensive set of sialylated glycans for binding to FH and solved the crystal structure of a ternary complex formed by the two C-terminal domains of FH, a sialylated trisaccharide and the complement C3b thioester-containing domain. Key residues in the sialic acid binding site are conserved from mice to men, and residues linked to atypical hemolytic uremic syndrome cluster within this binding site, suggesting a possible role for sialic acid as a host marker also in other mammals and a critical role in human renal complement homeostasis. Unexpectedly, the FH sialic acid binding site is structurally homologous to the binding sites of two evolutionarily unrelated proteins. The crystal structure also advances our understanding of bacterial immune evasion strategies. © 2015 Nature America, Inc. All rights reserved.

Kaye J.,University of Oxford | Curren L.,University of Oxford | Anderson N.,University of Washington | Edwards K.,University of Washington | And 8 more authors.
Nature Reviews Genetics | Year: 2012

Advances in computing technology and bioinformatics mean that medical research is increasingly characterized by large international consortia of researchers that are reliant on large data sets and biobanks. These trends raise a number of challenges for obtaining consent, protecting participant privacy concerns and maintaining public trust. Participant-centred initiatives (PCIs) use social media technologies to address these immediate concerns, but they also provide the basis for long-term interactive partnerships. Here, we give an overview of this rapidly moving field by providing an analysis of the different PCI approaches, as well as the benefits and challenges of implementing PCIs. © 2012 Macmillan Publishers Limited. All rights reserved.

Minelli C.,Institute of Genetic Medicine | Wei I.,Institute of Genetic Medicine | Sagoo G.,Institute of Genetic Medicine | Jarvis D.,Institute of Genetic Medicine | And 2 more authors.
American Journal of Epidemiology | Year: 2011

Susceptibility to the respiratory effects of air pollution varies between individuals. Although some evidence suggests higher susceptibility for subjects carrying variants of antioxidant genes, findings from gene-pollution interaction studies conflict in terms of the presence and direction of interactions. The authors conducted a systematic review on antioxidant gene-pollution interactions which included 15 studies, with 12 supporting the presence of interactions. For the glutathione S-transferase M1 gene (GSTM1) (n = 10 studies), only 1 study found interaction with the null genotype alone, although 5 observed interactions when GSTM1 was evaluated jointly with other genes (mainly NAD(P)H dehydrogenase [quinone] 1 (NQO1)). All studies on the glutathione S-transferase P1 (GSTP1) Ile105Val polymorphism (n = 11) provided some evidence of interaction, but findings conflicted in terms of risk allele. Results were negative for glutathione S-transferase T1 (GSTT1) (n = 3) and positive for heme oxygenase 1 (HMOX-1) (n = 2). Meta-analysis could not be performed because there were insufficient data available for any specific gene-pollutant-outcome combination. Overall the evidence supports the presence of gene-pollution interactions, although which pollutant interacts with which gene is unclear. However, issues regarding multiple testing, selective reporting, and publication bias raise the possibility of false-positive findings. Larger studies with greater accuracy of pollution assessment and improved quality of conduct and reporting are required. © The Author 2011.

Wong E.K.S.,Institute of Genetic Medicine | Kavanagh D.,Institute of Genetic Medicine
Translational Research | Year: 2015

The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor somatic mutations lead to a population of peripheral blood cells that are deficient in complement regulators resulting in hemolysis and thrombosis. In aHUS, germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation resulting in thrombotic microangiopathy and renal failure. Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS. © 2015 Elsevier Inc. All rights reserved.

Fairgrieve S.,Institute of Genetic Medicine
Nursing standard (Royal College of Nursing (Great Britain) : 1987) | Year: 2013

This is the eighth article in a series looking at how nurses can develop competence in genetics and genomics health care. The article explores the many ways in which nurses can acquire up to date and accurate genetic and genomic information, with the intention of improving their knowledge base. It enables nurses to discover the best ways of giving specific and complex information to patients and colleagues effectively and using straightforward language.

Kavanagh D.,Institute of Genetic Medicine | Smith-Jackson K.,Institute of Genetic Medicine
Kidney International | Year: 2016

Greenbaum et al. report the first prospective trial of eculizumab in pediatric atypical hemolytic uremic syndrome. As in adult trials, eculizumab appears effective and no serious safety signals were reported. There is the first suggestion of a dichotomy in response to treatment with a trend toward poorer outcome in those without complement abnormalities. This group, however, had worse renal function at presentation, and it remains to be seen whether this represents true non-response or merely late presentation. © 2016 International Society of Nephrology.

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